Cutaneous exposure to arsenicals causes vesicular skin lesions, blisters, and cutaneous inflammation, which progresses to multi-organ tissue damage and death. Lewisite, diphenylchlorarsine, diphenylcyanoarsine and diethylchloroarsine have been identified as potential threat chemicals by CounterACT (NIH) program for which antidotes/agents are needed. Preliminary data indicate that epigenetic pathways that are bromodomain 4 (BRD4)-dependent are up-regulated in multiple organs following cutaneous exposure to arsenicals. In addition, unfolded protein response (UPR) signaling is elevated under these conditions, which has been shown by the investigators to be associated with inflammatory responses. Preliminary data has also shown that necrosis regulators, such as receptor-interacting protein (RIP) kinases and the antioxidant, heme oxygenase-1 (HO-1), could be additional potential targets. The overall goal of the Drug Discovery and Development Core (DDC) is to collaborate with the investigators within the Research Center of Excellence in Arsenicals to identify and prioritize novel molecular target-based approaches to develop countermeasures for mitigating the effects of skin exposure to chemical vesicants. This will include the identification of novel small molecules that alleviate cutaneous injury, pulmonary and renal toxicity and testing of these compounds in vivo. The approach proposed herein will address the effective inhibition of several critical pathways and associated organ damage simultaneously. The DDC has expertise in compound screening and assay development, involving novel and diverse screening libraries which include over 4,000 FDA approved drugs. The core has a strong medicinal chemistry component with extensive experience in lead optimization and drug discovery, including computational and analytical chemistry and structural biology. Therefore, the major focus of these studies is on targeting novel inhibitory compounds of BRD4 as potential antidotes of arsenicals. Given that some of these targets may have tissue specificity (e.g., HO1 is critically associated with renal injury and is modulated in mice exposed to lewisite) and simultaneous inhibition of multiple targets may provide a more effective approach, we will also identify compounds affecting UPR, HO1 and RIP kinases. As compounds advance in in vitro and in vivo pharmacokinetic studies, pharmaceutics/formulations and toxicology will be applied to the programs. These combined capabilities provide the Center the ability to identify compounds suitable for IND-enabling studies. It will be the function of the DDC to support the Center by identifying the hit compounds and ultimately developing novel leads and potential clinically useful drugs with optimized biological and biophysical properties.